Preservative removal from eye drops

ABSTRACT

A particulate plug for removing a preservative from a solution, suspension, or emulsion comprising a drug is presented. The plug comprises microparticles of oxidized polyolefin (OxPO). The microparticles are irregular-shaped rigid aggregates and are sized and packed to yield a hydraulic permeability greater than 0.01 Da. The OxPO have absorbed portions of a preservative to be removed and/or a drug for delivery in solution, as can the copolymer.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.62/842,071 filed May 2, 2019, which is incorporated by reference in thedisclosure of this application.

BACKGROUND

Ophthalmic diseases are commonly treated with prescribed multi-dosemedications packaged in eye drop bottles due to ease of use,availability, affordability, and patient compliance. The frequency oftopical eye drop application varies from one or two times a day fordiseases like glaucoma to as many as ten times a day for severeinfections. Although eye drops formulations are packed under sterileconditions, the potential risk of contamination after prolonged use orimproper handling can be a key factor contributing to ocular infections.In some cases, as a frugal measure, multiple patients tend to use thesame multi-dose containers to administer medications, overlooking thepossibility of ocular infections due to cross-contamination,particularly if the protocol for disinfecting the nozzle is notfollowed. Most ophthalmic formulations now contain an added preservativeto maintain the shelf life of the sterile medication and eliminatemicrobial growth. The US Food and Drug Administration has imposedregulations on multi-dose ophthalmic formulations, mandating theaddition of preservatives to provide microbe-free medication. A varietyof preservatives are used to serve this purpose. Preservatives areneeded for maintaining sterility, but the benefit is often offset byadverse side effects of the preservatives, even among healthy subjects.

Benzalkonium chloride (BAK), a quaternary ammonium compound with highefficacy, is used prominently. BAK is an active detergent disinfectingagent, which interrupts the lipid membranes of cells, thereby inhibitingthe growth of microorganisms. Despite an acceptable tolerance and safetyprofile of BAK, many studies have shown commercial topical medicationswith added BAK content induce severe toxic side effects. Well-documentedadverse effects of BAK include tear film instability, trabecular andcorneal cells growth retardation and corneal and conjunctivalinflammation. Cytotoxicity studies show that BAK disrupts ocular surfacecells and tissues, whose impact in glaucoma and dry eye patientsrequiring long-term and frequent dosing is deleterious. Cornealendothelial damage occurs upon prolonged use of topical medication withadded benzalkonium chloride. High tear film instability and disruptionof the corneal barrier is observed using the preserved glaucoma drugTimolol to a greater extent than when using preservative-free Timolol inhealthy subjects. The detergent action of BAK solution disruptssuperficial lipid layers of the tear film into oil droplets solubilizedby a single drop of 0.01% BAK solution.

In 2009, the European Medicines Agency's Committee for MedicinalProducts for Human Use concluded that unpreserved formulations “areneeded for patients with lower tolerance to preservatives,” and “forlong-term treatment, formulations without preservatives are valuablealternatives.” Considering the adverse effects of preservatives, thedevelopment of safe eye drop dispensing devices to deliverpreservative-free formulations has been pursued for more than a decade.Preservative-free formulations are available in single-dose containersto eliminate the need for preservatives; however, these are notconvenient and too expensive for wide public use.

U.S. Pat. No. 5,080,800 teaches a process for removing components fromsolutions, including preservatives from eye-drops. The process involvesthe use of ion exchange resins to selectively remove ocularpreservatives. Ion exchange resins have not been tested extensively forbiocompatibility and cytotoxicity, and inherently are non-selective formolecules of same charge, adsorb ionic drugs as readily as any ionicpreservative such as BAK. The hydraulic permeability of these resins isnot addressed although this characteristic is critical for devices thatallow formation of drops without excessive pressure. U.S. Pat. No.5,080,800 does not teach on the importance of ensuring that the filtersare designed to resist growth of microorganisms that may remain trapped.U.S. Pat. No. 5,080,800 does not teach on the necessary requirements toensure that the concentration of the active drug in the drops coming outof the device do not fall below the minimum requirements based. Hence apractical way of retaining the beneficial behavior of preservativeswhile avoiding their toxic effects in the eye remains a need.

SUMMARY

Embodiments of the disclosure are directed to particulate plugs forselectively removing a large fraction of the preservative withoutsignificantly removing the drug and specifically directed to achievingthis for each eluting drop. The material of the plug may be designed tominimize drug binding. The material of the plug may depend on theproperties of the drug whose binding is to be minimized. The binding maydepend on the structure of the drug and/or the detailed structure of thematrix materials of the particles of the tip. Broadly, ophthalmic drugscan be divided into hydrophobic and hydrophilic categories depending ofthe affinity of the drug for water. Hydrophilic drugs are more solublein water while hydrophobic drugs are less soluble. By combining one ormore different monomers into the formulation for making the particles,the material may selectively remove a preservative while minimizingbinding of the drug.

Embodiments of the disclosure are directed to particulate plugs forremoving a preservative from a drug solution where microparticlescomprising the plug are oxidized polyolefins (OxPO). In some embodimentsthe OxPO is an oxidized polyethylene. In some embodiments the OxPO is anoxidized high density polyethylene (OxHDPE). The microparticles can beround, ovoid, smooth surfaced or irregular-shaped rigid aggregates thatform a particulate plug having a hydraulic permeability greater than0.01 Da and where the plug fits an outlet of a container for a solution,emulsion, or suspension. In some embodiments, the OxPO-comprising plugsfurther comprise absorbed portions of a preservative to be removedand/or a drug for delivery in solution, wherein the particulate plugrapidly and selectively removes a preservative from the solution,emulsion, or suspension.

The drug can be a hydrophilic drug, for example, Timolol Maleate,Levofloxacin, Dorzolamide, Brimonidine Tartrate, or and/or hydrophobicdrugs, for example, latanoprost or bimatoprost, and/or a combination ofhydrophilic drugs, for example, brimonidine and timolol (aka Combigan).The preservative may be Benzalkonium chloride (BAK).

Another embodiment of the disclosure is directed to a method of removinga preservative from a drug solution, where a container has an extendedoutlet and a chamber for holding a drug solution comprising at least onedrug and a preservative where the extended outlet is packed with aparticulate plug and the drug solution is forced through the particulateplug. The particulate plug can be preloaded with the drug or with thepreservative.

In an aspect, the present disclosure provides a particulate plug forremoving a preservative from a solution comprising a drug. The plug maycomprise microparticles of OxPO, wherein the microparticles are of anyshape and form a particulate plug having a hydraulic permeabilitygreater than 0.01 Da and fits an outlet of a container for a solution,emulsion, or suspension, wherein the OxPO optionally further comprisesabsorbed portions of a preservative to be removed and/or a drug fordelivery in solution, wherein the particulate plug rapidly andselectively removes a preservative from the solution, emulsion, orsuspension.

In another aspect, the present disclosure provides a method of removinga preservative from a drug solution, suspension, or emulsion. The methodmay comprise providing a container having an extended outlet and achamber for holding the drug solution, suspension, or emulsioncomprising at least one drug and a preservative; the containercomprising a particulate plug comprising OxPO within the extendedoutlet; and forcing the drug solution, suspension, or emulsion throughthe particulate plug.

In some embodiments, the method further comprises preloading theparticulate plug with the drug and/or with the preservative. In someembodiments, the drug comprises Timolol Maleate, Levofloxacin,Dorzolamide, Brimonidine Tartrate, or a combination thereof, such asbrimonidine and timolol (aka Combigan). In some embodiments, thepreservative is Benzalkonium chloride (BAK). In some embodiments, theplug comprises OxPO. In some embodiments, the plug comprises an OxPOselected from an OxHDPE.

In another aspect, the present disclosure provides a device for deliveryof a pharmaceutical formulation, the device comprising the particulateplug any embodiment and a pharmaceutical formulation comprising one ormore active components and a preservative, wherein when thepharmaceutical formulation is forced through the particulate plug atleast 90% of the preservative is selectively removed, while at least 90%of the one or more active components are retained in the deliveredpharmaceutical formulation.

In some embodiments, the device is an eye drop bottle for dispensingdrops of the pharmaceutical formulation and wherein the concentration ofthe one or more active components in a dispensed drop is at least 90% ofthat of the formulation inside the eye drop bottle, for every drop ofthe formulation forced through the plug. In some embodiments, theparticulate plug comprises a packed bed of particles. In someembodiments, the device has a holder assembly to retain the particulateplug while forcing the formulation through the plug. In someembodiments, the particulate plug comprises a formulation entry face anda formulation exit face, and the holder assembly comprises filters onthe solutions entry and exit faces of the particulate plug. In someembodiments, the holder assembly comprises a solution permeable bagaround the particulate plug. In some embodiments, the particulate plugis sintered to fuse the particulate plug as a porous monolith. In someembodiments, the particulate plug has a partition coefficient for thepreservative that is at least 100 and a partition coefficient for eachactive component that is less than 1. In some embodiments, theparticulate plug is pre-equilibrated with the drug. In some embodiments,the device further comprises packaging that holds the device in aposition for forcing the formulation through the particulate plug frommanufacture until the device is received by a patient for use.

In another aspect, the present disclosure provides a preservativeremoving device. The preservative removing device may comprisemicroparticles of OxPO, wherein the microparticles are of any shape,wherein the microparticles form a particulate plug having a hydraulicpermeability greater than 0.01 Da, wherein the plug fits an outlet of acontainer for a solution, emulsion, or suspension, wherein the OxPOfurther comprises absorbed portions of a preservative to be removed anda therapeutic agent for delivery, wherein the particulate plug rapidlyand selectively removes a preservative from the solution, emulsion, orsuspension.

In another aspect, the present disclosure provides a method of removinga preservative from a drug solution, suspension, or emulsion, accordingto any embodiment. The method may comprise providing a container havingan extended outlet and a chamber for holding the drug solution,suspension, or emulsion, the drug solution, suspension, or emulsioncomprising at least one drug and a preservative; wherein the containercomprises a particulate plug for removing the preservative from thesolution, suspension, or emulsion, the particulate plug within theextended outlet; and forcing the drug solution, suspension, or emulsionthrough the particulate plug. In some embodiments, the method furthercomprises preloading the particulate plug with the drug or with thepreservative.

In another aspect, the present disclosure provides a device for deliveryof a pharmaceutical formulation, comprising the particulate plug of anyembodiment and a pharmaceutical formulation comprising one or moreactive components and a preservative, wherein when the pharmaceuticalformulation is forced through the particulate plug at least 90% of thepreservative is selectively removed while at least 90% of all activecomponents are retained in the delivered pharmaceutical formulation.

In some embodiments, the device is an eye drop bottle for dispensingdrops of the pharmaceutical formulation and wherein the concentration ofthe active components in a dispensed drop is at least 90% of that of theformulation inside the eye drop bottle for every drop of the solutionforced through the plug. In some embodiments, the device has a holderassembly to retain the particulate plug while forcing the solutionthrough the particulate plug. In some embodiments, the particulate plugcomprises a formulation entry face and a formulation exit face, and theholder assembly comprises filters on the entry and exit faces of theparticulate plug. In some embodiments, the device further comprisespackaging that holds the device in a position for forcing the solution,suspension, or emulsion through the particulate plug from manufactureuntil the device is received by a patient for use.

Additional aspects and advantages of the present disclosure will becomereadily apparent to those skilled in this art from the followingdetailed description, wherein only illustrative embodiments of thepresent disclosure are shown and described. As will be realized, thepresent disclosure is capable of other and different embodiments, andits several details are capable of modifications in various obviousrespects, all without departing from the disclosure. Accordingly, thedrawings and description are to be regarded as illustrative in nature,and not as restrictive.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.To the extent publications and patents or patent applicationsincorporated by reference contradict the disclosure contained in thespecification, the specification is intended to supersede and/or takeprecedence over any such contradictory material.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe appended claims. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings of which:

FIG. 1 shows an example structure of Oxidized High Density Polyethylene(OxHDPE), in accordance with some embodiments.

FIG. 2 shows optical images of example Oxidized High DensityPolyethylene (OxHDPE) microparticles with 125-250 micron size on abackground grid of 100 microns, in accordance with some embodiments.

DETAILED DESCRIPTION

The present disclosure provides a preservative removal agent. Apreservative removal agent may rapidly and selectively removepreservatives of the present disclosure from a solution, emulsion, orsuspension comprising a therapeutic agent. The preservative removalagent may rapidly and selectively extract the preservative, allowing theeye drop formulation to flow through the plug with minimal pressuredrop, yet with sufficient time to remove the preservative and withsufficient surface area to adsorb the preservative. The matrix maycomprise a material with a high affinity for the preservative, such asfor example benzalkonium chloride (BAK), and low affinity for atherapeutic agent, such as a drug or other ophthalmological agent.

Aspects of the present disclosure provide a preservative removal agentwhich may comprise a porous polymer matrix. In some cases, thepreservative removal agent comprises OxPO. In some embodiments, the OxPOis an oxidized high-density polyethylene (OxHDPE).

The present disclosure provides a particulate plug for removing apreservative from a solution comprising a drug. The particulate plug maycomprise microparticles of an OxPO. The microparticles may beirregular-shaped rigid aggregates and may form a particulate plug havinga hydraulic permeability greater than 0.01 Darcy (Da). The plug may fitan outlet of a container for a solution, emulsion, or suspension. Insome cases, the OxPO microparticles further comprise absorbed portionsof a preservative to be removed and/or a drug for delivery in solution.The particulate plug may rapidly and selectively remove a preservativefrom the solution, emulsion, or suspension.

FIG. 1 shows an example structure of OxHDPE, in accordance with someembodiments.

FIG. 2 shows optical images of example OxHDPE microparticles with125-250 micron size on a background grid of 100 microns, in accordancewith some embodiments.

Preservative Removal Agent

In some embodiments, the disclosure provides pharmaceutical formulationscomprising a preservative and a therapeutic agent. The formulation maycomprise a solution, emulsion, or suspension of a therapeutic agent anda preservative. In some embodiments, the formulation may comprise apreservative removal agent, (e.g. in embodiments where the preservativeremoval agent may comprise a portion of a solution, emulsion, orsuspension comprising a therapeutic agent and a preservative). In otherembodiments, the preservative removal agent may be separate from thesolution, emulsion, or suspension comprising the therapeutic agent andthe preservative (e.g. in embodiments where the preservative removalagent may be located within the neck of a bottle). Optionally in anyembodiment, the solution, emulsion, or suspension may additionallycomprise one or more pharmaceutically acceptable excipients.

In some embodiments, a matrix disposed within a nozzle may be a porouspolymeric matrix. Applying a pressure behind the nozzle may cause fluidto flow through the nozzle via the flow path, along which path thepreservative may be removed by adsorption onto the matrix. The polymermaterial, the hydraulic permeability, the partition coefficient, theadsorption rate, and the pore size in combination provide for theabsorption of all, or most of, the preservative from the solution andthus from the drop administered to the patient eye. Thereduced-preservative solution may subsequently be delivered directly tothe eye. The porous polymeric matrix may rapidly and selectively extractthe preservative, allowing the eye drop formulation to flow through theplug with minimal pressure drop, yet with sufficient time to remove thepreservative and with sufficient surface area to adsorb thepreservative.

The porous polymeric matrix comprises oxidized polyolefin (OxPO)microparticles. An oxidized polyolefin is prepared by thermal and/orchemical degradation of a high molecular weight polyolefin resin. Theoxidation of polyolefins to form oxidized waxes is known in the art. Forexample, polyethylenes can be oxidized by the action of oxygen atelevated temperatures to obtain oxidized products through chaindegradation. (See, e.g., U.S. Pat. Nos. 3,293,112; 3,322,711; 4,459,388;and GB 1,087,915.) In one method, oxidation occurs while thepolyethylene is in the melt phase. Solid state oxidation is anothermethod for obtaining oxidized waxes from high molecular weightpolyolefin resins through chain degradation. (See, e.g., U.S. Pat. Nos.5,401,811; 5,064,908; 3,322,711 and 7,622,031.) It is understood thatthe inventions disclosed herein are not limited to homopolymers andcopolymers of ethylene. Also contemplated in the invention disclosedherein are other types of homopolymeric or copolymeric crystallizablepoly-alpha-olefins, such as, homopolymers and copolymers of propylene,1-butene, 4-methyl-1-pentene, 3-methyl-1-butene, 4,4-dimethyl-1-pentene,3-methyl-1-pentene, 4-methyl-1-hexene, 5-ethyl-1-hexene,6-methyl-1-heptene, 1-hexene, 1-heptene, 1-octene, 1-nonene, 1-decene,and the like. Also included are oxidized waxes formed by theFischer-Tropsch process. While these linear polymethylenes are nottechnically polyolefins, their structure is practically identical topolyethylene. Such material may be safe and biocompatible. The matrixcomprises a material with a high affinity for the preservative, such asfor example benzalkonium chloride (BAK), and low affinity for a drug orother ophthalmological agent. In some embodiments, the porous OxPOpolymeric matrix exhibits a high affinity for the preservative, suchthat at least 50 percent of the preservative may be removed and at least50 percent of the drug may be retained by the solution. In someembodiments, a matrix disposed within a nozzle may be a porous polymericmatrix.

The process of oxidation of an oxidized polyolefin may be characterizedby an acid number. The progress of the oxidation can be determined byseveral methods, such acid number by titration or instrumental methodssuch as Fourier transform infrared (FTIR) spectroscopy or Near Infrared(NIR) spectroscopy. The porous polymeric matrix may comprise oxidizedpolyolefin (OxPO) microparticles with an acid value of about 30. Theporous polymeric matrix may comprise an acid number of at least 4, fromabout 10 to about 50, from about 20 to about 40, etc. The porouspolymeric matrix may comprise oxidized high density polyethylene with anacid value of about 30 mgKOH/g as measured by DIN EN ISO 2114.

An oxidized polyolefin may be characterized by a drop point, e.g. a meltpoint. A melt point of an oxidized polyolefin may relate to a chainlength, a degree of oxidation, etc. The porous polymeric matrix maycomprise oxidized polyolefin (OxPO) microparticles with a drop pointbetween 125 and 135 Celsius. The porous polymeric matrix may compriseoxidized polyolefin (OxPO) microparticles with a drop point of about 50to about 200° C., from about 100 to about 150° C., from about 125 toabout 135° C., etc. The porous polymeric matrix may comprise oxidizedhigh density polyethylene with a drop point between 125 and 135 Celsiusas measured by DGF M-III 3.

An oxidized polyolefin may be characterized by a density. The density ofthe polymer may increase as the extent of oxidation increase. Withoutintending to be bound by theory, this may be the result of thesubstitution of heavier oxygen atoms for lighter hydrogen atoms in thepolymer. An exact value in any instance may depend on the initialdensity of the starting polymer and the extent of oxidation. Density maymeasured by gradient column, for example, according to ASTM D1505-68 or-85, DIN 51579, etc. The porous polymeric matrix may comprise oxidizedpolyolefin (OxPO) microparticles with a density above about 0.910 g/cm3,from about 0.930 to about 1.210 or higher g/cm3, from about 0.940 toabout 1.000 g/cm3, about 0.98, etc. The porous polymeric matrix maycomprise oxidized high density polyethylene with a density of about 0.98grams per cubic centimeter as measured by DIN 51579.

An oxidized polyolefin may be characterized by a viscosity. Theviscosity of the polymer may vary with the degree of oxidation. Forexample, high molecular weight polyethylene of the feedstock may undergooxidation to form polyethylene waxes of relatively lower molecularweight. The porous polymeric matrix may comprise oxidized polyolefin(OxPO) microparticles with a viscosity above about 100 microPascalseconds, between about 1 milliPascalseconds (mPas) and about 10 mPas,between about 2 mPas and about 6 mPas, and about 4 mPas. The porouspolymeric matrix may comprise oxidized high density polyethylene with adensity of about of 4.00 mPas at 190 Celsius as measured by DIN ENISO3104.

In some embodiments, the matrix displays a high hydraulic permeabilitysuch that relatively little pressure is required to dispense a fluid.The hydraulic permeability may depend on the design of the filter.Larger pores may allow for higher flow for a given pressure drop. Insome embodiments, hydraulic permeability is larger than about 0.01Darcy. A nozzle may comprise a permeability of about 0.1 Darcy. Ahydraulic permeability of 1 to 10 Darcy may allow fluid to be retainedin the filter during instances when the pressure may be loweredsubsequent to formation of a drop. A larger hydraulic permeability mayallow the same plug to work for a wide range of formulations including,for example, high viscosity formulations, such as rewetting eye drops.In some embodiments, the porous polymeric matrix comprises a hydraulicpermeability of, for example, 0.01 Da, 0.1 Da, 1 Da, 10 Da, 100 Da, 1000Da or a hydraulic permeability within a range defined by any two of thepreceding values.

In some embodiments, the matrix may be highly porous containing largechannels through which liquid can flow. The pore or channel size in thematrix may be small enough so that the molecules, which may initially befar from the surface of the polymer in the matrix, may diffuse towardsthe polymer and adsorb. A matrix may comprise large interconnected poresor channels which may allow flow of solution and adsorption of thepreservative into the pores or channels. The matrix may be formed as aporous gel, as a packed bed, and/or a structure formed by 3D printingsoft lithography, electrospinning, or any other appropriate method. Insome embodiments, the matrix may comprise a microporous gel. In someembodiments, the matrix comprises a packed bed of OxPO polymericparticles. The particles may be macroporous. The particles may bespherical or non-spherical. In some embodiments, the polymeric matrixmay comprise nano-sized or micron-sized polymeric particles (e.g.,nanogels or microgels).

In some embodiments, the particles may need to be stably held in thenozzle from which the formulation elutes from a container and therebyprevented from eluting from the nozzle. In some cases, the matrix may besintered to fuse the particulate plug into porous monolith. In somecases, the device may have a cartridge or other assembly to retain thematrix in the nozzle. The device may have a solution permeable bag toretain the matrix. The device may comprise solid walls with a solutionpermeable bottom. The device may comprise entrance and exit faces with amatrix material therebetween. The entrance and exit faces may comprisesolution permeable membranes. The entry and exit faces may comprise afilter. The entrance and exit faces may comprise a screen. The particlesmay be attached to the container walls through long polymeric chainsand/or by placing a filter at the exit from the device. The device maycomprise a packaging for delivery to a patient. The packaging may securethe device such that the device may not be compressed until the deviceis delivered to the patient. The packaging may secure the exit face fromallowing the formulation to exit the bottle. The packaging may comprisea removable cap, a break-off cap, a resealable cap, etc.

In certain embodiments, particles described herein have an averagelargest dimension from about 1 nm to about 10 μm, about 1 nm to about 5μm, about 1 nm to about 2 μm, about 1 nm to about 1 μm, about 1 nm toabout 900 nm, about 1 nm to about 800 nm, about 1 nm to about 700, about1 nm to about 600 nm, about 1 nm to about 500 nm, about 1 nm to about400 nm, about 1 nm to about 300 nm, about 1 nm to about 200 nm, or evenfrom about 1 nm to about 100 nm. In certain embodiments, the averagelargest dimension is the average largest diameter or the averageequivalent diameter.

In certain embodiments, greater than 80%, greater than 90% or greaterthan 95% of the particles in the formulation have an average largestparticle diameter of from about 1 nm to about 10 μm, about 1 nm to about5 μm, about 1 nm to about 2 μm, about 1 nm to about 1 μm, about 1 nm toabout 900 nm, about 1 nm to about 800 nm, about 1 nm to about 700 nm,about 1 nm to about 600 nm, about 1 nm to about 500 nm, about 1 nm toabout 400 nm, about 1 nm to about 300 nm, about 1 nm to about 200 nm, oreven from about 1 nm to about 100 nm. In certain embodiments, theaverage diameter is the average largest diameter or the averageequivalent diameter.

In certain embodiments, particles described herein have an averagediameter from about 100 nm to about 10 μm, about 100 nm to about 5 μm,about 100 nm to about 2 μm, about 100 nm to about 1 μm, about 100 nm toabout 900 nm, about 100 nm to about 800 nm, about 100 nm to about 700nm, about 100 nm to about 600 nm, about 200 nm to about 500 nm, about250 nm to about 600 nm, about 300 nm to about 600 nm, about 350 nm toabout 700 nm, about 450 nm to about 550 nm, about 475 nm to about 525nm, or from about 400 nm to about 700 nm. In certain embodiments, theaverage diameter is the average largest diameter or the averageequivalent diameter.

In certain embodiments, greater than 80%, greater than 90% or greaterthan 95% of the particles in the formulation have an average diameterfrom about 100 nm to about 10 μm, about 100 nm to about 5 μm, about 100nm to about 2 μm, about 100 nm to about 1 μm, about 100 nm to about 900nm, about 100 nm to about 800 nm, about 100 nm to about 700 nm, about100 nm to about 600 nm, about 200 nm to about 500 nm, about 250 nm toabout 600 nm, about 300 nm to about 600 nm, about 350 nm to about 700nm, about 450 nm to about 550 nm, about 475 nm to about 525 nm, or fromabout 400 nm to about 700 nm. In certain embodiments, the averagediameter is the average largest diameter or the average equivalentdiameter.

The matrix may comprise a tortuosity such that the flow path of asolution, emulsion, or suspension through the nozzle may besignificantly increased. In an embodiment where the matrix is a packedbed of macroporous particles, the packed beds of macroporous particlesmay have two or three levels of porosity: the space between theparticles, the macropores in the particles, and the inherent porosity ofthe polymer. In some embodiments, all levels of porosity may contributeto the tortuosity of the matrix.

Therapeutic Agent

Embodiments of the present disclosure provide at least one therapeuticagent for delivery to an eye. A therapeutic agent is integrated into afluid, which flows from a container through a nozzle comprising a porouspolymeric matrix comprising oxidized polyolefin (OxPO) microparticles toan eye. In some embodiments, the fluid may comprise a solution,emulsion, or suspension comprising at least one therapeutic agent. Thesolution, emulsion, or suspension may comprise more than one therapeuticagent.

Example therapeutic agents which may be used in conjunction with anozzle comprising a porous polymeric matrix comprising oxidizedpolyolefin (OxPO) microparticles include but are not limited to:timolol, dorzolamide, dexamethoasone phosphate, dexamethasone, Betimol®,olopatadine, brimonidine, tetrahydrozoline, latanoprostene bunod,latanoprost, and combinations of thereof. Therapeutic agents maycomprise brand name drugs and formulations including, but not limitedto, Timoptic, Xalatan, Combigan, Lumigan, Pataday, Pazeo, Trusopt,Cosopt, Alphagan, Visine, Vyzulta, Veseneo, and other agents describedherein such as in the following tables. The therapeutic agents may bedissolved in aqueous solution. The solution may be sterilized andbuffered to appropriate pH. In some embodiments, the solution maycomprise inactive ingredients such as sodium chloride, sodium citrate,hydroxyethyl cellulose, sodium phosphate, citric acid, sodium dihydrogenphosphate, polyoxyl 40 hydrogenated castor oil, tromethamine, boricacid, mannitol, edetate disodium, sodium hydroxide, and/or hydrochloricacid. In some embodiments, the fluid comprises a preservative inaddition to a therapeutic agent. Example preservatives include but arenot limited to: benzalkonium chloride (BAK), alcohols, parabens, methylparaben, propylparaben, EDTA, chlorhexidine, quaternary ammoniumcompounds, Purite®, stabilized oxychloro complexes, Sofzia®, sorbicacid, Sodium perborate, polyquaternium-1, chlorobutanol, cetrimoniumchloride, edetate disodium, etc. In some embodiments, the preservativeis benzalkonium chloride (BAK). In some embodiments, the preservative isquaternary ammonium compounds. In some embodiments, the preservative ispolyquaternium-1. In some embodiments, the preservative is cetrimoniumchloride.

Therapeutic agents for the treatment of, for example, dry eye, bacterialinfection, glaucoma, hypertension, inflammation, allergicconjunctivitis, hypotrichosis of the eyelashes, fungal infection, etc.and therapeutic agents used for local anesthetic, pupil dilation, etc.may be administered to a patient as a solution, emulsion, or suspensiondelivered to an eye topically via a dropper bottle or similar deliverymechanism. The solution, emulsion, or suspension may be subject tocontamination such as microbial, fungal, or particulate contamination,which may be adverse to patient health. In order to prevent suchcontamination a preservative may be added to the solution, emulsion, orsuspension; however, patient exposure to preservatives may have adverseeffects to eye health.

The present disclosure provides one or more therapeutic agentsformulated with a preservative capable of being removed by apreservative removing device of the present disclosure. Therapeuticagents may comprise compounds and salts, for use in the treatment ofophthalmic diseases. The disclosed compounds and salts can be used, forexample, for the treatment or prevention of vision disorders and/or foruse during ophthalmological procedures for the prevention and/ortreatment of ophthalmic disorders. The following list of examples arenot intended to be limiting.

In some embodiments, the at least one therapeutic agent to be dispensedcomprises an active ingredient selected from cyclosporine andlifitegrast. In some embodiments, the therapeutic agent may be an activeingredient in the treatment of dry eye.

In some embodiments, the at least one therapeutic agent to be dispensedcomprises an active ingredient selected from sulfacetamide sodium,ofloxacin, gatifloxacin, ciprofloxacin, moxifloxacin, tobramycin,levofloxacin, prednisolone acetate, polymyxin B sulfate, andtrimethoprim. In some embodiments, the therapeutic formulation to bedispensed comprises the active ingredients sulfacetamide sodium andprednisolone acetate. In some embodiments, the therapeutic formulationto be dispensed comprises the active ingredients polymyxin B sulfate andtrimethoprim. In some embodiments, the therapeutic agent may be anactive ingredient in the treatment of a bacterial infection.

In some embodiments, the at least one therapeutic agent to be dispensedcomprises an active ingredient selected from brimonidine tartrate,bimatoprost, levobunolol hydrochloride, brinzolamide, betaxololhydrochloride, pilocarpine hydrochloride, apraclonidine, travoprost,timolol maleate, latanoprost, dorzolamide hydrochloride, and tafluprost.In some embodiments, the therapeutic formulation to be dispensedcomprises the active ingredients brimonidine tartrate and timololmaleate. In some embodiments, the therapeutic formulation to bedispensed comprises the active ingredients brinzolamide and brimonidinetartrate. In some embodiments, the therapeutic agent may be an activeingredient in the treatment of glaucoma or hypertension.

In some embodiments, the at least one therapeutic agent to be dispensedcomprises an active ingredient selected from ketorolac tromethamine,fluorometholone, prednisolone acetate, difluprednate, fluorometholoneacetate, nepafenac, dexamethasone, diclofenac sodium, bromfenac,gentamicin, tobramycin, neomycin, and polymyxin B sulfate. In someembodiments, the therapeutic formulation to be dispensed comprises theactive ingredients gentamicin and prednisolone acetate. In someembodiments, the therapeutic formulation to be dispensed comprises theactive ingredients tobramycin and dexamethasone. In some embodiments,the therapeutic formulation to be dispensed comprises the activeingredients neomycin, polymyxin B sulfate and dexamethasone. In someembodiments, the therapeutic agent may be an active ingredient in thetreatment of inflammation.

In some embodiments, the at least one therapeutic agent to be dispensedcomprises an active ingredient selected from nedocromil sodium,epinastine HCl, alcaftadine, lodoxamide tromethamine, emedastinedifumarate, and olopatadine hydrochloride. In some embodiments, thetherapeutic agent may be an active ingredient in the treatment ofallergic conjunctivitis.

In some embodiments, the at least one therapeutic agent to be dispensedcomprises an active ingredient selected from proparacaine hydrochlorideand tetracaine hydrochloride. In some embodiments, the therapeutic agentmay be a local anesthetic.

In some embodiments, the at least one therapeutic agent to be dispensedcomprises an active ingredient selected from cyclopentolatehydrochloride, atropine sulfate, and tropicamide. In some embodiments,the therapeutic formulation to be dispensed comprises the activeingredients cyclopentolate hydrochloride and phenylephrinehydrochloride. In such embodiments, the therapeutic agent may dilatepupils.

In some embodiments, the at least one therapeutic agent to be dispensedcomprises the active ingredient natamycin. In such embodiments, thetherapeutic agent may be an active ingredient in the treatment of fungalinfection.

In some embodiments, the at least one therapeutic agent to be dispensedcomprises an active ingredient selected from lipoic acid choline esterchloride, rebamipide, pilocarpine, aceclidine, tropicamide, sodiumhyaluronate, diclofenac sodium, pilocarpine HCl, and ketorolac. In someembodiments, the therapeutic formulation to be dispensed comprises theactive ingredients aceclidine and tropicamide. In some embodiments, thetherapeutic formulation to be dispensed comprises the active ingredientssodium hyaluronate and diclofenac sodium and pilocarpine HCl. In someembodiments, the therapeutic formulation to be dispensed comprises theactive ingredients pilocarpine and ketorolac. In some embodiments, thetherapeutic agent may be an active ingredient in the treatment ofpresbyopia.

In some embodiments, the at least one therapeutic agent to be dispensedis a therapeutic agent selected from Tables 1 to 4.

TABLE 1 Therapeutic Agent Sorted by Indication Market % ActiveFormulation Name Drug Ingredient Type Indication Preservative Dry EyeRestasis Cyclosporine 0.05%  emulsion keratoconjunctivitis none siccaXiidra Lifitegrast   5% solution keratoconjunctivitis none sicca VisineTetrahydrozoline keratoconjunctivitis sicca Bacterial Infection Bleph 10sulfacetamide  10% solution conjunctivitis and benzalkonium sodium otherocular chloride infections 0.005% Blephamide sulfacetamide  10%/0.2%suspension bacterial ocular benzalkonium sodium— infection chlorideprednisolone 0.004% acetate Ocuflox Ofloxacin 0.3% solution bacterialocular benzalkonium infection; corneal chloride ulcers (0.005%) Polytrimpolymyxin B polymyxin B solution ocular bacterial benzalkonium sulfateand sulfate 10,000 infections; chloride 0.04 trimethoprim units/mL;conjunctivitis; mg/mL trimethoprim blepharo- sulfate conjunctivitisequivalent to 1 mg/mL Zymaxid Gatifloxacin 0.3% and solution bacterialbenzalkonium 0.5% conjunctivitis chloride 0.005% Zymar Gatifloxacin 0.3%solution bacterial benzalkonium conjunctivitis chloride 0.005%; CiloxanCiprofloxacin 0.3% solution bacterial None conjunctivitis MoxezaMoxifloxacin 0.5% solution bacterial none conjunctivitis TobrexTobramycin 0.3% solution infections of the eye benzalkonium and itsadnexa caused chloride by susceptible 0.01% bacteria VigamoxMoxifloxacin 0.5% solution bacterial none conjunctivitis IquixLevofloxacin 1.5% solution bacterial benzalkonium conjunctivitischloride 0.005% Quixin Levofloxacin 0.5% solution bacterial benzalkoniumconjunctivitis chloride 0.005% Glaucoma or Hypertension Alphaganbrimonidine 0.01%  solution open-angle glaucoma Purite ® tartrate orocular 0.005% (0.05 hypertension mg/mL) Lumigan Bimatoprost 0.01% solution open angle glaucoma benzalkonium or ocular chloride 0.2hypertension mg/mL Betagan levobunolol 0.5% solution chronic open-anglebenzalkonium hydrochloride glaucoma or ocular chloride hypertension0.004% Combigan brimonidine 0.2%/0.5% solution glaucoma or ocularbenzalkonium tartrate/timolol hypertension who chloride maleate requireadjunctive or 0.005% replacement therapy due to inadequately controlledIOP Azopt Brinzolamide   1% suspension ocular hypertension benzalkoniumor open-angle chloride 0.1 glaucoma mg Betoptic S betaxolol 0.25% andsuspension ocular hypertension benzalkonium hydrochloride 0.5% orchronic open angle chloride glaucoma 0.1 mg in 1 mL Isopto pilocarpine1%, 2% solution IOP reduction; open- benzalkonium Carpine hydrochlorideand 4% angle glaucoma or chloride ocular hypertension; 0.01% acuteangle-closure glaucoma; induction of miosis Iopidine Apraclonidine 0.5%and solution Short term adjunctive benzalkonium 1.0% therapy in patientson chloride maximally tolerated 0.01% medical therapy who requireadditional IOP reduction Simbrinza brinzolamide/   1%/0.2% suspensionreduction of elevated benzalkonium brimonidine IOP in patients withchloride 0.03 tartrate open-angle glaucoma mg or ocular hypertensionTravatan Z Travoprost 0.004%  solution open-angle glaucoma ionicbuffered or ocular system, hypertension who are sofZia intolerant ofother intraocular pressure lowering medications Isralol Timolol maleate0.5% solution ocular hypertension benzalkonium or open-angle chloride0.05 glaucoma mg/mL Xalatan Latanoprost approximately solutionopen-angle glaucoma benzalkonium 1.5 μg per or ocular chloride, drophypertension 0.02% Trusopt dorzolamide   2% solution ocular hypertensionbenzalkonium hydrochloride or open-angle chloride glaucoma 0.0075%Timoptic timolol maleate 0.25% and solution ocular hypertensionbenzalkonium 0.5% or open-angle chloride glaucoma Ziotan Tafluprost0.0015%   solution open-angle glaucoma none or ocular hypertensionVesneo Latanoprostene glaucoma Bunod Vyzulta Latanoprostene glaucomaBunod Cosopt Dorzolamide + Glaucoma Timolol Inflammation Acular LSketorolac 0.4% solution ocular pain and benzalkonium tromethamineburning/stinging chloride following corneal 0.006% refractive surgeryAcular ketorolac 0.5% solution inflammation benzalkonium tromethaminefollowing cataract chloride surgery; relief of 0.01% ocular itching dueto seasonal allergic conjunctivitis Acuvail ketorolac 0.45%  solutiontreatment of pain and none tromethamine inflammation following cataractsurgery FML Forte Fluorometholone 0.25%  ointment corticosteroid-benzalkonium responsive chloride inflammation of the 0.005% palpebraland bulbar conjunctiva, cornea and anterior segment of the globe FMLFluorometholone 0.1% suspension corticosteroid- benzalkonium responsivechloride inflammation of the 0.004% palpebral and bulbar conjunctiva,cornea and anterior segment of the globe Pred Forte prednisolone   1%suspension steroid-responsive benzalkonium acetate inflammation of thechloride palpebral and bulbar conjunctiva, cornea, and anterior segmentof the globe Pred Mild prednisolone 0.12%  suspension mild to moderatebenzalkonium acetate noninfectious allergic chloride and inflammatorydisorders of the lid, conjunctiva, cornea, and sclera, includingchemical and thermal burns Pred-G gentamicin and 0.3%/1%   suspensionsteroid-responsive Benzalkonium prednisolone inflammatory; chlorideacetate bacterial infection; 0.005% thermal burns or penetration offoreign bodies Durezol Difluprednate 0.05%  emulsion inflammation andsorbic acid pain associated with 0.1% ocular surgery Flarexfluorometholone 0.1% suspension steroid-responsive benzalkonium acetateinflammatory chloride conditions of the 0.01% palpebral and bulbarconjunctiva, cornea and anterior segment of the eye Ilevro Nepafenac0.3% suspension pain and benzalkonium inflammation chloride associatedwith 0.005% cataract surgery Maxidex Dexamethasone 0.1% suspensionSteroid responsive benzalkonium inflammatory chloride conditions;corneal 0.01% injury from chemical, radiation, or thermal bums, orpenetration of foreign bodies Maxitrol neomycin and neomycin solutionsteroid-responsive methylparaben polymyxin B sulfate inflammatory ocular0.05%, sulfates and equivalent to conditions for which propylparabendexamethasone neomycin a corticosteroid is 0.01% 3.5 mg, indicated andwhere polymyxin B bacterial infection or sulfate 10,000 a risk ofbacterial units, ocular infection dexamethasone exists 0.1% NevanacNepafenac 0.1% suspension pain and benzalkonium inflammation chlorideassociated with 0.005% cataract surgery Omnipred prednisolone 1.0%suspension steroid responsive benzalkonium acetate inflammatory chlorideconditions; corneal 0.01% injury from chemical, radiation, or thermal offoreign bodies Tobradex tobramycin/  0.3%/0.05% suspensionsteroid-responsive benzalkonium ST dexamethasone inflammatory ocularchloride 0.1 conditions for which mg a corticosteroid is indicated andwhere superficial bacterial ocular infection exists Voltaren diclofenac0.1% solution inflammation from None Ophthalmic sodium cataractextraction; temporary relief of pain and photophobia following cornealrefractive surgery Bromday Bromfenac 0.09%  solution postoperativebenzalkonium inflammation in chloride 0.05 patients who have mg/mLundergone cataract extraction Xibrom Bromfenac 0.09%  solutionpostoperative benzalkonium inflammation in chloride (0.05 patients whohave mg/mL) undergone cataract extraction Xibrom Bromfenac 0.09% solution postoperative benzalkonium inflammation in chloride 0.05patients who have mg/mL undergone cataract extraction AllergicConjunctivitis Alocril nedocromil   2% solution itching associatedbenzalkonium sodium with allergic chloride conjunctivitis 0.01% Elestatepinastine HCl 0.05%  suspension itching associated Benzalkonium withallergic chloride conjunctivitis 0.01%; Lastacaft Alcaftadine 0.25% solution itching associated benzalkonium with allergic chlorideconjunctivitis 0.005% Alomide lodoxamide 0.1% solution vernalbenzalkonium tromethamine keratoconjunctivitis; chloride giant papillary0.007% w/v conjunctivitis; allergic/atopic conjunctivitis Emadineemedastine 0.5% solution allergic conjunctivitis benzalkonium difumaratechloride, 0.01% Pataday olopatadine 0.2% solution ocular itchingbenzalkonium hydrochloride associated with chloride allergicconjunctivitis 0.01% Pazeo olopatadine 0.7% solution ocular itchingbenzalkonium hydrochloride associated with chloride allergicconjunctivitis 0.015% Hair Growth Latisse Bimatoprost 0.03%  solutionhypotrichosis of the benzalkonium eyelashes chloride 0.05 mg/mL LocalAnesthetic Alcaine proparacaine 0.5% solution topical anesthesia—benzalkonium hydrochloride removal of foreign chloride bodies;measurement 0.01% of intraocular pressure; conjunctive scrapingTetracaine Tetracaine 0.5% solution procedures requiring Nonehydrochloride a rapid and short acting topical ophthalmic anestheticPupil Dilation Cyclogyl cyclopentolate 0.5%, 1.0% solution pre- andpost- Benzalkonium hydrochloride or 2.0% operative states when chloridemydriasis is required 0.1 mg in and when a shorter 1.0 mL actingmydriatic and cycloplegic is needed in the therapy of iridocyclitisCyclomydril cyclopentolate 0.2%/1.0% solution For the production ofBenzalkonium hydrochloride mydriasis (pupil chloride and dilation) 0.01%phenylephrine hydrochloride Isopto atropine sulfate   1% solutionmydriasis; benzalkonium Atropine cycloplegia; chloride penalization ofthe 0.01% healthy eye in the treatment of amblyopia MydriacylTropicamide 0.5% or 1.0% solution mydriasis and benzalkonium cycloplegiachloride 0.01% Fungal infection Natacyn Natamycin   5% suspensionanti-fungal; fungal benzalkonium blepharitis, chloride conjunctivitis,and 0.02% keratitis

TABLE 2 Presbyopia Formulations % Active Formulation Drug Code DrugIngredient Type Indication Preservative Presbyopia EV06/ lipoic acid3.0% solution presbyopia benzalkonium UNR844 choline ester chloride,chloride 0.01% PRX-100 aceclidine/ 0.25-2.0%/ Solution or benzalkoniumtropicamide 0.025-0.1% suspension presbyopia chloride, 0.02% CSF-1sodium 0.1-0.9%/ Solution or presbyopia Any, hyaluronate/ 0.006-0.012%/suspension benzalkonium diclofenac 0.2-0.4% chloride, sodium/ 0.01%pilocarpine HCl AAGN- Pilocarpine 0.1%-1% Solution or presbyopia Any,199201 and/or suspension benzalkonium oxymetazoline chloride, 0.01%AAGN- keterolac 0.1%-1% Solution or presbyopia Any, 190584 suspensionbenzalkonium chloride, 0.01%

TABLE 3 Additional Therapeutic Agents % Active Formulation Market NameDrug Ingredient Type Indication Preservative Restasis cyclosporine0.05%  emulsion keratoconjunctivitis none sicca Latisse bimatoprost0.03%  solution hypotrichosis of the benzalkonium eyelashes chloride0.05 mg/mL Alphagan brimonidine 0.01%  solution open-angle glaucomaPurite ® Tartrate or ocular 0.005% (0.05 hypertension mg/mL) Lumiganbimatoprost 0.01%  solution open angle glaucoma benzalkonium or ocularchloride 0.2 hypertension mg/mL Acular LS ketorolac 0.4% solution ocularpain and benzalkonium tromethamine burning/stinging chloride followingcorneal 0.006% refractive surgery Acular ketorolac 0.5% solutioninflammation benzalkonium tromethamine following cataract chloride 0.01%surgery; relief of ocular itching due to seasonal allergicconjunctivitis Acuvail ketorolac 0.45%  solution treatment of pain andnone tromethamine inflammation following cataract surgery Alocrilnedocromil   2% solution itching associated benzalkonium sodium withallergic chloride 0.01% conjunctivitis Betagan levobunolol 0.5% solutionchronic open-angle benzalkonium hydrochloride glaucoma or ocularchloride hypertension 0.004% Bleph 10 sulfacetamide  10% solutionconjunctivitis and benzalkonium sodium other ocular chloride infections0.005% Blephamide sulfacetamide  10%/0.2% suspension bacterial ocularbenzalkonium sodium— infection chloride prednisolone 0.004% acetateCombigan brimonidine 0.2%/0.5% solution glaucoma or ocular benzalkoniumtartrate/timolol hypertension who chloride maleate require adjunctive or0.005% replacement therapy due to inadequately controlled iop Elestatepinastine HCl 0.05%  suspension itching associated benzalkonium withallergic chloride conjunctivitis 0.01%; FML Forte fluorometholone 0.25% ointment corticosteroid- benzalkonium responsive chloride inflammationof the 0.005% palpebral and bulbar conjunctiva, cornea and anteriorsegment of the globe FML fluorometholone 0.1% suspension corticosteroid-benzalkonium responsive chloride inflammation of the 0.004% palpebraland bulbar conjunctiva, cornea and anterior segment of the globeLastacaft alcaftadine 0.25%  solution itching associated benzalkoniumwith allergic chloride conjunctivitis 0.005% Ocuflox ofloxacin 0.3%solution bacterial ocular benzalkonium infection; corneal chlorideulcers (0.005%) Polytrim polymyxin B polymyxin B solution ocularbacterial benzalkonium sulfate and sulfate infections; chloride 0.04trimethoprim 10,000 conjunctivitis; mg/mL units/mL; blepharo-trimethoprim conjunctivitis sulfate equivalent to 1 mg/mL Pred Forteprednisolone   1% suspension steroid-responsive benzalkonium acetateinflammation of the chloride palpebral and bulbar conjunctiva, cornea,and anterior segment of the globe Pred Mild prednisolone 0.12% suspension mild to moderate benzalkonium acetate noninfectious allergicchloride and inflammatory disorders of the lid, conjunctiva, cornea, andsclera, including chemical and thermal burns Pred-G gentamicin and0.3%/1%   suspension steroid-responsive benzalkonium prednisoloneinflammatory; chloride acetate bacterial infection; 0.005% thermal burnsor penetration of foreign bodies Zymaxid gatifloxacin 0.3% and solutionbacterial benzalkonium 0.5% conjunctivitis chloride 0.005% Zymargatifloxacin 0.3% solution bacterial benzalkonium conjunctivitischloride 0.005%; Alcaine proparacaine 0.5% solution topical anesthesia—benzalkonium hydrochloride removal of foreign chloride 0.01% bodies;measurement of intraocular pressure; conjunctive scraping Alomidelodoxamide 0.1% solution vernal benzalkonium tromethaminekeratoconjunctivitis; chloride giant papillary 0.007% w/vconjunctivitis; allergic/atopic conjunctivitis Azopt brinzolamide   1%suspension ocular hypertension benzalkonium or open-angle chloride 0.1mg glaucoma Betoptic S betaxolol 0.25% and suspension ocularhypertension benzalkonium hydrochloride 0.5% or chronic open anglechloride 0.1 mg glaucoma in 1 mL Ciloxan ciprofloxacin 0.3% solutionbacterial None conjunctivitis Cyclogyl cyclopentolate 0.5%, 1.0%solution pre- and post- benzalkonium hydrochloride or 2.0% operativestates when chloride 0.1 mg mydriasis is required in 1.0 mL and when ashorter acting mydriatic and cycloplegic is needed in the therapy ofiridocyclitis Cyclomydril cyclopentolate 0.2%/1.0% solution for theproduction of benzalkonium hydrochloride and mydriasis (pupil chloride0.01% phenylephrine dilation) hydrochloride Durezol difluprednate 0.05% emulsion inflammation and sorbic acid pain associated with 0.1% ocularsurgery Emadine emedastine 0.5% solution allergic conjunctivitisbenzalkonium difumarate chloride, 0.01% Flarex fluorometholone 0.1%suspension steroid-responsive benzalkonium acetate inflammatory chloride0.01% conditions of the palpebral and bulbar conjunctiva, cornea andanterior segment of the eye Ilevro nepafenac 0.3% suspension pain andbenzalkonium inflammation chloride associated with 0.005% cataractsurgery Iopidine apraclonidine 0.5% and solution short term adjunctivebenzalkonium 1.0% therapy in patients on chloride 0.01% maximallytolerated medical therapy who require additional iop reduction Isoptoatropine sulfate   1% solution mydriasis; benzalkonium Atropinecycloplegia; chloride 0.01% penalization of the healthy eye in thetreatment of amblyopia Isopto Carpine pilocarpine 1%, 2% and solutioniop reduction; open- benzalkonium hydrochloride   4% angle glaucoma orchloride 0.01% ocular hypertension; acute angle-closure glaucoma;induction of miosis Maxidex dexamethasone 0.1% suspension steroidresponsive benzalkonium inflammatory chloride conditions; corneal 0.01%injury from chemical, radiation, or thermal bums, or penetration offoreign bodies Maxitrol neomycin and neomycin solutionsteroid-responsive methylparaben polymyxin B sulfate inflammatory ocular0.05%, sulfates and equivalent to conditions for which propylparabendexamethasone neomycin a corticosteroid is 0.01% 3.5 mg, indicated andwhere polymyxin B bacterial infection or sulfate a risk of bacterial10,000 units, ocular infection dexamethasone exists 0.1% Moxezamoxifloxacin 0.5% solution bacterial None conjunctivitis Mydriacyltropicamide 0.5% or 1.0% solution mydriasis and benzalkonium cycloplegiachloride 0.01% Natacyn natamycin   5% suspension anti-fungal; fungalbenzalkonium blepharitis, chloride 0.02% conjunctivitis, and keratitisNevanac nepafenac 0.1% suspension pain and benzalkonium inflammationchloride associated with 0.005% cataract surgery Omnipred prednisolone1.0% suspension steroid responsive benzalkonium acetate inflammatorychloride 0.01% conditions; corneal injury from chemical, radiation, orthermal bums, or penetration of foreign bodies Pataday olopatadine 0.2%solution ocular itching benzalkonium hydrochloride associated withchloride 0.01% allergic conjunctivitis Pazeo olopatadine 0.7% solutionocular itching benzalkonium hydrochloride associated with chlorideallergic conjunctivitis 0.015% Simbrinza brinzolamide/   1%/0.2%suspension reduction of elevated benzalkonium brimonidine iop inpatients with chloride tartrate open-angle glaucoma 0.03 mg or ocularhypertension Tetracaine hydrochloride 0.5% solution procedures requiringNone a rapid and shortacting topical ophthalmic anesthetic Tobradex STtobramycin/  0.3%/0.05% suspension steroid-responsive benzalkoniumdexamethasone inflammatory ocular chloride 0.1 mg conditions for which acorticosteroid is indicated and where superficial bacterial ocularinfection exists Tobrex tobramycin 0.3% solution infections of the eyebenzalkonium and its adnexa caused chloride 0.01% by susceptiblebacteria Travatan Z travoprost 0.004%  solution open-angle glaucomaionic buffered or ocular system, sofZia hypertension who are intolerantof other intraocular pressure lowering medications Vigamox moxifloxacin0.5% solution bacterial None conjunctivitis Voltaren diclofenac sodium0.1% solution inflammation from None Ophthalmic cataract extraction;temporary relief of pain and photophobia following corneal refractivesurgery Trusopt dorzolamide   2% solution ocular hypertensionbenzalkonium hydrochloride or open-angle chloride glaucoma 0.0075%Timoptic timolol maleate 0.25% and solution ocular hypertensionbenzalkonium 0.5% or open-angle chloride glaucoma Ziotan tafluprost0.0015%   solution open-angle glaucoma none or ocular hypertensionXalatan latanoprost approximately solution open-angle glaucomabenzalkonium 1.5 μg per or ocular chloride, drop hypertension 0.02%Bromday bromfenac 0.09%  solution postoperative benzalkoniuminflammation in chloride 0.05 patients who have mg/mL undergone cataractextraction Isralol timolol maleate 0.5% solution ocular hypertensionbenzalkonium or open-angle chloride 0.05 glaucoma mg/mL Xibrom bromfenac0.09%  solution postoperative benzalkonium inflammation in chloride(0.05 patients who have mg/mL) undergone cataract extraction Iquixlevofloxacin 1.5% solution bacterial benzalkonium conjunctivitischloride 0.005% Quixin levofloxacin 0.5% solution bacterial benzalkoniumconjunctivitis chloride 0.005% Xibrom bromfenac 0.09%  solutionpostoperative benzalkonium inflammation in chloride 0.05 patients whohave mg/mL undergone cataract extraction Xiidra lifitegrast   5%solution Dry Eye None

TABLE 4 Other Therapeutic Agents Code of Drug in Clinical % ActiveFormulation Trial Drug Ingredient Type Indication Preservative EV06/lipoic acid 3.0% solution presbyopia benzalkonium UNR844 choline esterchloride, 0.01% chloride PRX-100 aceclidine/ 0.25-2.0%/ Solution orpresbyopia benzalkonium tropicamide 0.025-0.1% suspension chloride,0.02% SF-1 sodium 0.1-0.9%/ Solution or presbyopia Any, hyaluronate/0.006-0.012%/ suspension benzalkonium diclofenac 0.2-0.4% chloride,0.01% sodium/ pilocarpine HCl ECF843 0.1%-1% Solution or Dry eye Any,suspension benzalkonium chloride, 0.01% None rebamipide 1%, 2% solutionDry eye Any, (keratoconjunctivitis benzalkonium sicca) chloride, 0.01%AAGN- Pilocarpine 0.1%-1% Solution or presbyopia Any, 199201 and/orsuspension benzalkonium oxymetazoline chloride, 0.01% AAGN- keterolac0.1%-1% Solution or presbyopia Any, 190584 suspension benzalkoniumchloride, 0.01% pilocarpine 0.3% Solution or presbyopia Any, suspensionbenzalkonium chloride, 0.01% pilocarpine varies with Solution orpresbyopia Any, severity of suspension benzalkonium presbyopia,chloride, 0.01% 0.3%-2.2%Preservative

The present disclosure provides one or more preservatives for solutions,emulsions, or suspensions of therapeutic agents of the presentdisclosure. Preservatives may comprise compounds and salts, for use aspreservatives for solutions, emulsions, or suspensions of therapeuticagents. The one or more preservatives may for example prevent microbialand/or fungal growth. The one or more preservatives may for exampleprevent physical or chemical deterioration of a therapeutic agent.

Non-limiting examples of preservative agents include benzalkoniumchloride, ethylenediaminetetraacetic acid (EDTA), or the sodium salt ofEDTA, chlorobutanol, phenylmercuric acetate, phenylmercuric nitrate,chlorhexidine acetate, thimerosal, benzethonium chloride, sorbic acid,alcohols, parabens (e.g., methylparaben, polyparaben), chlorhexidine,quaternary ammonium compounds, polyquaternium-1 (Polyquad®) Purite®,stabilized oxychloro complexes, Sofzia®, sodium perborate (GenAqua®),cetrimonium chloride, edetate disodium, etc. In some embodiments, thepreservative is benzalkonium chloride. In some embodiments, thepreservative is a quaternary ammonium compound. In some embodiments, thepreservative is polyquaternium-1. In some embodiments, the preservativeis cetrimonium chloride.

In some embodiments, the particulate plug may further include apreservative removing compound or a preservative deactivating compound.Preservative removing or deactivating compounds can decrease toxicity ofa formulation to be delivered through typical separation methodsincluding, but not limited to, adsorption, ion exchange, chemicalprecipitation, or solvent extraction. Preservative removing ordeactivating compounds can include, but are not limited to, activatedcharcoal, antioxidants, ethylenediaminetetraacetic acid (EDTA), anionichydrogels, cationic compounds, neutralizing agents, or combinationsthereof.

The Purite® preservative system includes Stabilized Oxychloro Complex(SOC), a combination of chlorine dioxide, chlorite and chlorate. Whenexposed to light, SOC dissociates into water, oxygen, sodium andchlorine free radicals which cause oxidation of intracellular lipids andglutathione, interrupting vital enzymes for cell function andmaintenance. For preservatives such as Purite® which produce chlorinefree radicals, the particulate plug of the disclosure can include amaterial that has a high affinity for free radicals such as activatedcharcoal or antioxidants such as vitamin E.

The SofZia® preservative system in Travatan Z (Alcon Laboratories, FortWorth, Tex.) contains borate, sorbitol, propylene glycol, and zinc.Without intending to be bound by theory, it is believed that thepreservative effect is from a combination of borate and zinc. Forpreservatives including borate and zinc, such as SofZia®, theparticulate plug of the disclosure can include a metal chelating agentsuch as EDTA, anionic hydrogels that can extract cationic zinc throughelectrostatic interactions, cationic hydrogels or resins that canextract anionic borate ions through electrostatic interactions, or aneutralizing agent that can neutralize boric acid.

The materials that can sequester the preservative can be incorporatedinto the particulate plug as microparticles, such as particles ofactivated charcoal. The microparticles can be packed into theparticulate plug such that the liquid has sufficient space in betweenthe particles to flow out, while also providing sufficient contact areafor binding. Alternatively, the sequestering materials could beincorporated into particles of other suitable materials such as thepolymer particles of the disclosure to facilitate the contact betweenthe eluding formulation and the sequestering material. In some cases,the sequestration material, can be integrated into the polymercovalently. The sequestering material can be a nanoparticle or can beincorporated into a nanoparticle, which could in turn be dispersed intothe polymer particles that form a packed bed in the tip. Thenanoparticle could also be deposited just on the surface of the largerparticles. The sequestering material could also form tubes that can bearranged in parallel to provide the path for liquid to flow out andsequestration to occur on the surface.

The materials present in the particulate plug to neutralize the freeradicals in the formulation, for example, vitamins, can be incorporatedinto the polymer particles that form the particulate plug. Bases can beincorporated to bring the pH to a level that is comfortable in the eyes.The polymer particles can be loaded with vitamin E for example bysoaking the particles in a solution of vitamin E dissolved in an organicliquid, leading to uptake of vitamin E into the particles. Subsequently,the organic liquid such as ethanol can be evaporated or extracted intowater to form particles loaded with vitamin E. The material of theparticles that is loaded with vitamin E could be chosen to achieve otherbeneficial purposes such as extraction of some other component of thepreservative.

The preservative effect of the formulations can be improved byincorporation of another preservative such as Benzalkonium Chloride sothat the formulation can pass EPA criterion as well. The added BAK orthe other preservative can be removed by the particulate plug to achieveimproved preservative performance without increasing toxicity.

The particulate plug including a preservative removing compound orpreservative deactivating compound can be formed in various shapes suchas spheres, cylinders, tubes, highly irregular, flat sheets etc, wherethe surface could be rough or smooth. The particles or other shapesintegrated into the tip can contain some preservative to ensure that thetip itself remains sterile. The preservative pre-loaded into the tipcould be loaded via adsorption or be chemically attached to the materialthrough a bond. For example, Polyquaternium can be integrated into thepolymer forming the particles. The covalent attachment will preventdiffusion of the pre-loaded preservative into the tear film.Alternatively, the pre-loaded preservative could be sufficiently largein molecular weight or have very low partitioning into the eludingformulation.

In cases wherein the particulate plug including a preservative removingcompound or a preservative deactivating compound is intended to add acomponent to the eluding formulation, the amount of that material in theparticulate plug will be sufficiently large to ensure that there issufficient amount remaining for the entire bottle, or at least 90% ofthe bottle. In cases wherein the particulate plug including apreservative removing compound or a preservative deactivating compoundis intended to sequester a component from the eluding formulation, thevolume and area in the particulate plug will be sufficiently large tosequester the desired component from at least 90% of the formulation inthe bottle.

The present disclosure provides salts of any one or both of atherapeutic agent and a preservative. Pharmaceutically-acceptable saltsinclude, for example, acid-addition salts and base-addition salts. Theacid that is added to the compound to form an acid-addition salt can bean organic acid or an inorganic acid. A base that is added to thecompound to form a base-addition salt can be an organic base or aninorganic base. In some embodiments, a pharmaceutically-acceptable saltis a metal salt.

Metal salts can arise from the addition of an inorganic base to acompound of the present disclosure. The inorganic base consists of ametal cation paired with a basic counterion, such as, for example,hydroxide, carbonate, bicarbonate, or phosphate. The metal can be analkali metal, alkaline earth metal, transition metal, or main groupmetal. In some embodiments, the metal is lithium, sodium, potassium,cesium, cerium, magnesium, manganese, iron, calcium, strontium, cobalt,titanium, aluminum, copper, cadmium, or zinc.

In some embodiments, a metal salt is a lithium salt, a sodium salt, apotassium salt, a cesium salt, a cerium salt, a magnesium salt, amanganese salt, an iron salt, a calcium salt, a strontium salt, a cobaltsalt, a titanium salt, an aluminum salt, a copper salt, a cadmium salt,or a zinc salt.

Acid addition salts can arise from the addition of an acid to a compoundof the present disclosure. In some embodiments, the acid is organic. Insome embodiments, the acid is inorganic. In some embodiments, the acidis hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid,nitrous acid, sulfuric acid, sulfurous acid, a phosphoric acid,isonicotinic acid, lactic acid, salicylic acid, tartaric acid, ascorbicacid, gentisinic acid, gluconic acid, glucuronic acid, saccharic acid,formic acid, benzoic acid, glutamic acid, pantothenic acid, acetic acid,propionic acid, butyric acid, fumaric acid, succinic acid,methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, citric acid, oxalic acid, or maleic acid.

In some embodiments, the salt is a hydrochloride salt, a hydrobromidesalt, a hydroiodide salt, a nitrate salt, a nitrite salt, a sulfatesalt, a sulfite salt, a phosphate salt, isonicotinate salt, a lactatesalt, a salicylate salt, a tartrate salt, an ascorbate salt, agentisinate salt, a gluconate salt, a glucuronate salt, a saccharatesalt, a formate salt, a benzoate salt, a glutamate salt, a pantothenatesalt, an acetate salt, a propionate salt, a butyrate salt, a fumaratesalt, a succinate salt, a methanesulfonate (mesylate) salt, anethanesulfonate salt, a benzenesulfonate salt, a p-toluenesulfonatesalt, a citrate salt, an oxalate salt, or a maleate salt.

Solution, Emulsion, or Suspension

Provided herein are solutions, emulsions, or suspensions of atherapeutic agent and a preservative. In some embodiments, providedherein are compositions comprising a therapeutically effective amount ofany compound or salt of any one of the preservatives and/or therapeuticagents of the present disclosure. In some embodiments, a therapeuticsolution, emulsion, or suspension may be used in any of the methodsdescribed herein. The solution, emulsion, or suspension may additionallycomprise one or more pharmaceutically acceptable excipients.

In some embodiments, a compound of preservative and/or therapeutic agentmay be used for the treatment of a therapeutic disorder such as, dryeye, bacterial infection, glaucoma, hypertension, inflammation, allergicconjunctivitis, hypotrichosis of the eyelashes, fungal infection, etc.Additionally or alternatively, a compound of a preservative and/ortherapeutic agent may be used during a preventative, diagnostic, ortherapeutic ophthalmological procedure, for example, local anesthetic,pupil dilation, etc. A formulation administered to the eye may beadministered topically, for example, with an eye drop.

A compound of the therapeutic agent described herein can be present in asolution, emulsion, or suspension of the present disclosure at aconcentration of, for example, about 500 nM, about 600 nM, about 700 nM,about 800 nM, about 900 nM, about 1 μM, about 2 μM, about 3 μM, about 4μM, about 5 μM, about 6 μM, about 7 μM, about 8 μM, about 9 μM, about 10μM, about 20 μM, about 30 μM, about 40 μM, about 50 μM, about 60 μM,about 70 μM, about 80 μM, about 90 μM, about 100 μM, about 150 μM, about200 μM, about 250 μM, about 300 μM, about 350 μM, about 400 μM, about450 μM, about 500 μM, about 550 μM, about 600 μM, about 650 μM, about700 μM, about 750 μM, about 800 μM, about 850 μM, about 900 μM, about 1mM, about 5 mM, about 10 mM, about 15 mM, about 20 mM, about 25 mM,about 30 mM, about 35 mM, about 40 mM, about 45 mM, about 50 mM, about55 mM, about 60 mM, about 65 mM, about 70 mM, about 75 mM, about 80 mM,about 85 mM, about 90 mM, about 95 mM, or about 100 mM. The compound ofa therapeutic agent described herein may be present in a solution,emulsion, or suspension within a range of concentrations, the rangebeing defined by an upper and lower value selected from any of thepreceding concentrations. For example, the compound or salt of atherapeutic agent of the disclosure may be present in the solution,emulsion, or suspension at a concentration of from about 1 nM to about100 mM, about 10 nM to about 10 mM, about 100 nM to about 1 mM, about500 nM to about 1 mM, about 1 mM to about 50 mM, about 10 mM to about 40mM, about 20 mM to about 35 mM, or about 20 mM to about 30 mM.

In some embodiments, a solution, emulsion, or suspension such as anaqueous solution of the disclosure, comprises from about 0.001 wt % toabout 0.3 wt % of the compound of any one of the preservatives disclosedherein. In some embodiments, a solution, emulsion, or suspension such asan aqueous solution of the disclosure, comprises about 0.001 wt %, about0.002 wt %, about 0.003 wt %, about 0.004 wt %, about 0.005 wt %, about0.006 wt %, about 0.007 wt %, about 0.008 wt %, about 0.009 wt %, about0.01 wt %, about 0.02 wt %, about 0.03 wt %, about 0.04 wt %, about 0.05wt %, about 0.06 wt %, about 0.07 wt %, about 0.08 wt %, about 0.09 wt%, about 0.1 wt %, about 0.2 wt %, about 0.3 wt %, about 0.4 wt %, about0.5 wt %, about 0.6 wt %, about 0.7 wt %, about 0.8 wt %, about 0.9 wt%, about 1 wt %, about 1.1 wt %, about 1.2 wt %, about 1.3 wt %, about1.4 wt %, about 1.5 wt %, about 1.6 wt %, about 1.7 wt %, about 1.8 wt%, about 1.9 wt %, about 2 wt %, about 3 wt %, about 4 wt %, about 5 wt%, about 6 wt %, about 7 wt %, about 8 wt %, about 9 wt %, or about 10wt % of a compound of the preservative described herein.

The preservative described herein can be present in a solution,emulsion, or suspension of the present disclosure at a concentration of,for example, about 500 nM, about 600 nM, about 700 nM, about 800 nM,about 900 nM, about 1 μM, about 2 μM, about 3 μM, about 4 μM, about 5μM, about 6 μM, about 7 μM, about 8 μM, about 9 μM, about 10 μM, about20 μM, about 30 μM, about 40 μM, about 50 μM, about 60 μM, about 70 μM,about 80 μM, about 90 μM, about 100 μM, about 150 μM, about 200 μM,about 250 μM, about 300 μM, about 350 μM, about 400 μM, about 450 μM,about 500 μM, about 550 μM, about 600 μM, about 650 μM, about 700 μM,about 750 μM, about 800 μM, about 850 μM, about 900 μM, about 1 mM,about 5 mM, about 10 mM, about 15 mM, about 20 mM, about 25 mM, about 30mM, about 35 mM, about 40 mM, about 45 mM, about 50 mM, about 55 mM,about 60 mM, about 65 mM, about 70 mM, about 75 mM, about 80 mM, about85 mM, about 90 mM, about 95 mM, or about 100 mM. The compound of apreservative described herein may be present in a composition within arange of concentrations, the range being defined by an upper and lowervalue selected from any of the preceding concentrations. For example,the compound of a preservative of the disclosure may be present in thesolution, emulsion, or suspension at a concentration of from about 1 nMto about 100 mM, about 10 nM to about 10 mM, about 100 nM to about 1 mM,about 500 nM to about 1 mM, about 1 mM to about 50 mM, about 10 mM toabout 40 mM, about 20 mM to about 35 mM, or about 20 mM to about 30 mM.

Solutions, emulsions, or suspensions of the disclosure can be formulatedat any suitable pH. In some embodiments, the pH of the solution emulsionor suspension is about 4, about 4.05, about 4.1, about 4.15, about 4.2,about 4.25, about 4.3, about 4.35, about 4.4, about 4.45, about 4.5,about 4.55, about 4.6, about 4.65, about 4.7, about 4.75, about 4.8,about 4.85, about 4.9, about 4.95, about 5, about 5.1, about 5.2, about5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9,about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about6.6, about 6.7, about 6.8, about 6.9, about 7, about 7.1, about 7.2,about 7.3, about 7.4, about 7.5, about 7.6, about 7.7, about 7.8, about7.9, about 8, about 8.1, about 8.2, about 8.3, about 8.4, about 8.5,about 8.6, about 8.7, about 8.8, about 8.9, or about 9 pH units. In someembodiments, the pH of the solution, emulsion, or suspension is fromabout 4 to about 10, about 5 to about 9, about 6 to about 8, about 6.5to about 8, about 7 to about 8, about 7.2 to about 8, about 7.2 to about7.8, about 7.3 to about 7.5, or about 7.35 to about 7.45. In someembodiments the pH of the solution, emulsion, or suspension is about7.4.

In some embodiments, solutions, emulsions, or suspensions of the presentdisclosure further comprise one or more physiologically acceptablecarriers including excipients and auxiliaries which facilitateprocessing of the pharmaceutical agent into preparations which are usedpharmaceutically. Proper formulation is dependent upon the route ofadministration chosen.

In some embodiments, the addition of an excipient to a pharmaceuticalformulation of the present disclosure can increase or decrease theviscosity of the composition by at least 5%, at least 10%, at least 15%,at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, atleast 45%, at least 50%, at least 55%, at least 60%, at least 65%, atleast 70%, at least 75%, at least 80%, at least 85%, at least 90%, atleast 95%, or at least 99%. In some embodiments, the addition of anexcipient to a pharmaceutical formulation of the present disclosure canincrease or decrease the viscosity of the composition by no greater than5%, no greater than 10%, no greater than 15%, no greater than 20%, nogreater than 25%, no greater than 30%, no greater than 35%, no greaterthan 40%, no greater than 45%, no greater than 50%, no greater than 55%,no greater than 60%, no greater than 65%, no greater than 70%, nogreater than 75%, no greater than 80%, no greater than 85%, no greaterthan 90%, no greater than 95%, or no greater than 99%. Examples ofranges which the viscosity change falls within can be created bycombining any two of the preceding percentages. For example, theaddition of an excipient can increase or decrease the viscosity of thecomposition by 5% to 99%, by 10% to 95%, by 20% to 70% or by 35% to 55%.

In some embodiments, solutions, emulsions, or suspensions of the presentdisclosure further comprise an agent for adjusting the osmolarity of thesolution, emulsion, or suspension, e.g., mannitol, sodium chloride,sodium sulfate, dextrose, potassium chloride, glycerin, propyleneglycol, calcium chloride, and magnesium chloride. In some embodiments,the solution, emulsion, or suspension comprises from about 0.1 wt % toabout 10 wt %, about 0.5 wt % to about 8 wt %, about 1 wt % to about 5wt %, about 1 wt % to about 4 wt %, or about 1 wt % to about 3 wt % ofan agent for adjusting the osmolarity of the solution, emulsion, orsuspension. In some embodiments, the solution, emulsion, or suspensionof the disclosure has an osmolarity from about 10 mOsm to about 1000mOsm, about 100 mOsm to about 700 mOsm, about 200 mOsm to about 400mOsm, about 250 mOsm to about 350 mOsm or even about 290 mOsm to about310 mOsm.

The amount of the excipient in a solution, emulsion, or suspension ofthe present disclosure can be about 0.01%, about 0.02%, about 0.03%,about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.5%, about2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%,about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%,about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about55% about 60%, about 65%, about 70%, about 75%, about 80%, about 85%,about 90%, about 95%, about 99%, or about 100% by mass or by volume ofthe unit dosage form. The amount of the excipient in a solution,emulsion, or suspension can be between 0.01% and 1000%, between 0.02%and 500%, between 0.1% and 100%, between 1% and 50%, between 0.01% and1%, between 1% and 10%, between 10% and 100%, between 50% and 150%,between 100% and 500%, or between 500% and 1000% by mass or by volume ofthe unit dosage form.

The ratio of a compound of a therapeutic agent of the present disclosureto an excipient in a pharmaceutical formulation of the presentdisclosure can be about 100:about 1, about 95:about 1, about 90:about 1,about 85:about 1, about 80:about 1, about 75:about 1, about 70:about 1,about 65:about 1, about 60:about 1, about 55:about 1, about 50:about 1,about 45:about 1, about 40:about 1, about 35:about 1 about 30:about 1,about 25:about 1, about 20:about 1, about 15:about 1, about 10:about 1,about 9:about 1, about 8:about 1, about 7:about 1, about 6:about 1,about 5:about 1, about 4:about 1, about 3:about 1, about 2:about 1,about 1:about 1, about 1:about 2, about 1:about 3, about 1:about 4,about 1:about 5, about 1:about 6, about 1:about 7, about 1:about 8,about 1:about 9, or about 1:about 10. The ratio of a compound of atherapeutic agent to an excipient in a solution, emulsion, or suspensionof the present disclosure can be within the range of between about100:about 1 and about 1 to about 10, between about 10:about 1 and about1:about 1, between about 5:about 1 and about 2:about 1.

Pharmaceutically acceptable carriers are well known in the art andinclude, for example, aqueous solutions such as water or physiologicallybuffered saline or other solvents or vehicles such as glycols, glycerol,oils such as olive oil, or organic esters. The excipients can be chosen,for example, to effect delayed release of an agent or to selectivelytarget one or more cells, tissues or organs. The composition can also bepresent in a solution suitable for topical administration, such as aneye drop.

In some embodiments, the solution emulsion or suspension provided hereincomprises an alcohol as an excipient. Non-limiting examples of alcoholsinclude ethanol, propylene glycol, glycerol, polyethylene glycol,chlorobutanol, isopropanol, xylitol, sorbitol, maltitol, erythritol,threitol, arabitol, ribitol, mannitol, galactilol, fucitol, lactitol,and combinations thereof.

Methods for the preparation of compositions comprising the compoundsdescribed herein can include formulating the compounds with one or moreinert, pharmaceutically-acceptable excipients. Liquid compositionsinclude, for example, solutions in which a compound is dissolved,emulsions comprising a compound, or a solution containing liposomes,micelles, or nanoparticles comprising a compound as disclosed herein.These compositions can also contain minor amounts of nontoxic, auxiliarysubstances, such as wetting or emulsifying agents, pH buffering agents,and other pharmaceutically-acceptable additives.

Examples

Hydrophilic Drugs

Calculating the Partition Coefficient of API and BAK in the ParticleMatrix

The partition coefficients of hydrophilic drugs and BAK in OxPOparticles are obtained by drug uptake studies. The mass of drug or BAKpartitioned into OxPO matrix is determined by monitoring the amount ofdrug or BAK lost in the concentrated aqueous drug/PBS or BAK/PBS loadingsolutions. The amount of drug loss from the concentrated aqueous phasewas quantified by time-dependent measurements using reverse phase UPLCanalysis.

The partition coefficient of drug or BAK solution in the particle matrixis given by

$\begin{matrix}{{k = {\frac{C_{p,f}}{C_{w,f}} = \frac{V_{w}\left( {C_{w,f} - C_{w,i}} \right)}{V_{p}C_{w,f}}}},} & \left( {{Equation}\mspace{14mu} 1} \right)\end{matrix}$where V_(w) and V_(p) are volumes of drug-PBS/BAK-PBS aqueous solutionand volume of the particle matrix respectively, C_(p,f) and C_(w,f)denote the drug or BAK concentration in the particle matrix and aqueousphase at equilibrium, and C_(w,i) represents the initial concentrationof the drug or BAK loading solution.

A more accurate estimate BAK diffusivity is obtained by fitting theexperimental BAK uptake data to a transient diffusion model undernon-perfect sink conditions. The transport of solute through these OxPOmaterials occurred through swelling of the polymer, bulk and surfacediffusion. To maintain the model's simplicity, we assumed preservativediffusion through the filter material to be purely Fickian. Assuming theBAK diffusivity, D_(g) and partition coefficient K are independent ofconcentration of BAK, transport in the radial direction can be describedas:

$\begin{matrix}{{\frac{\partial C_{g}}{\partial t} = {D_{g}\left( {\frac{\partial^{2}C_{g}}{\partial r^{2}} + {\frac{2}{r}\frac{\partial C_{g}}{\partial r}}} \right)}},} & \left( {{Equation}\mspace{14mu} 2} \right)\end{matrix}$where C_(g) is the BAK concentration in the OxPO particle matrix. Theboundary and initial conditions for diffusion in the particle matrix are

$\begin{matrix}{{\frac{\partial C_{g}}{\partial y_{2}}\left( {y_{2} = 0} \right)} = 0} & \left( {{Equation}\mspace{14mu} 3} \right) \\{{C\left( {y_{2} = h_{g}} \right)} = {{KC}_{f}(t)}} & \left( {{Equation}.\mspace{14mu} 4} \right) \\{{C_{g}\left( {t = 0} \right)} = 0} & \left( {{Equation}.\mspace{14mu} 5} \right)\end{matrix}$

The boundary condition (Equation 3) arises from symmetry of the particlematrix and that in (Equation 4) assumes equilibrium betweenconcentration of the preservative in the polymer matrix and thesurrounding formulation present in the aqueous BAK solution in the vial.A mass balance on the aqueous BAK reservoir in the scintillation vialyields the following equation:

$\begin{matrix}{{V_{w}\frac{{dC}_{w}}{dt}} = {{- D_{g}}A_{g}n_{d}\frac{\partial C_{g}}{\partial r}\left( {r = R} \right)}} & \left( {{Equation}\mspace{14mu} 6} \right) \\{{{V_{w}\frac{{dC}_{w}}{dt}} = {{- D_{g}}\frac{3V_{g}}{R}\frac{\partial C_{g}}{\partial r}\left( {r = R} \right)}},} & \left( {{Equation}\mspace{14mu} 7} \right)\end{matrix}$where V_(w) is the volume of BAK/PBS solution in the aqueous reservoirwhose concentration is 1 mg/mL. The modelled diffusion equation issolved using finite difference schemes in MATLAB with BAK diffusivityand partition coefficient determined by curve fitting experimental BAKuptake data for different OxPO compositions to the model andoptimization through fminsearch module.

The partition coefficients of hydrophilic drugs and BAK in OxPOparticles is determined by reverse phase UPLC analysis.

Oxidized Low Density Polyethylene (OxLDPE) and Oxidized High DensityPolyethylene (OxHDPE) are commercially available from Honeywell (e.g.A-C 395) and DEUREX (e.g. DEUREX EO 45). Oxidized Fischer-Tropsch Wax(OxFTW) is available from DEUREX (e.g. DEUREX TO-84). Several differentgrades of these OxPOs are available; they are typically characterized bytheir molecular weight, drop point (melting point), density, hardness,particle size and acid number (mg KOH/g).

BAK (pharma grade) was obtained from Sigma-Aldrich (St. Lewis, Mo.); itwas a mixture of approximately 70% C12 and 30% C14Benzylalkyldimethylammonium Chloride. Research grade Timolol Maleate andBrimonidine Tartrate were obtained from BOC Sciences (Shirley, N.Y.).Phosphate Buffered Saline (PBS) was obtained from Fisher Scientific.Hydroxyethyl Cellulose (Natrosol 250H) was obtained from AshlandChemical. Mannitol was obtained from JT Baker Co.

Washing Procedure for OxPOs

Approximately 70 g of OxHDPE (Honeywell's A-C 395A; sieved fraction at63-125 um) was added to a 2 L beaker on a stirrer hotplate containing 1L of 0.1 N aq. acetic acid. The mixture was heated with stirring for 1 hat 65-70° C. The product was collected on a 63 μm sieve and thoroughlywashed with about 3 L of DI water. The washed OxHDPE was dried in avacuum oven at ambient temperature to yield about 65 g of white powder.The BAK partition coefficient of this powder was determined to be 360.Other OxPOs were washed in a similar manner. The wash solution waseither neutral water, 0.1 N aq. acetic acid or 0.1 N aq. ammoniumhydroxide.

Ultra Performance Liquid Chromatography (UPLC):

The UPLC system consisted of a Waters Aquity UPLC (Waters, Milford,Mass., US) equipped with a Binary pump, online degasser, column heater,autosampler and UV/Vis detector. Data collection and analysis wereperformed using Empower 3 FR 4 (Waters). Separation was achieved on aWaters UPLC, HSS C18 1.8 μm, 3.0 mm×100 mm column protected using aWaters HSS C18 1.8 um, VanGuard Pre-Column.

For the APIs Timolol and Brimonidine, the flow rate was 1.0 ml/min,solvent A was acetonitrile and solvent B was 0.1% Trifluoroacetic Acid.For the first 0.40 min, the solvent was 10% A/90% B; the next 1.4 minthe gradient ramped to 100% A; held at 100% A for 2.2 min; switched backto 10% A/90% B. Total run time 3.5 min. The results for UPLC wererecorded on UV-Vis (λ=256 nm and 297 nm) detectors.

For BAK, the flow rate was 0.75 ml/min, solvent A was acetonitrile andsolvent B was 0.03N HCl. For the first 1.0 min, the solvent was 60%A/40% B; the next 3.5 min the gradient ramped to 90% A/10% B; held at90% A/10% B for 0.5 min.; the next 0.2 min the gradient ramped to 20%A/80% B; then switched back to 60% A/40% B. Total run time 7.0 min. Theresults for UPLC were recorded on UV-Vis (λ=210 nm) detectors.

Prior to analysis of target drugs and BAK, standards were made todetermine the UV absorbances. A 3D spectrum was collected and theoptimal UV wavelength was selected. Based on the area counts the targetsample was then diluted within the linear range. To determine the linearrange a series of standards were made and then plotted onto a graph, thegraph was then fitted with a linear trendline. The trendline was set togo through the 0 intercept and if the linear fit was above 0.9900 thedilution was determined to be adequate.

Procedure for Determining the BAK Partition Coefficient

To a 20 ml scintillation vial was added 0.2 g of the OxPO being testedand 5.0 ml of a 1000 ppm BAK solution in normal PBS. The vial was cappedand swirled on a rotary shaker for 2 days. The supernatant solution wasfiltered through a 0.45 micron filter to remove any solids. A portion ofthe filtrate was diluted 1:1 with acetonitrile and analyzed by UPLC asdescribed above.

Procedure for Determining the API Partition Coefficient

To a 20 ml scintillation vial was added 0.1 g of the OxPO being testedand 5.0 ml of an API formulation. The vial was capped and swirled on arotary shaker for 2 days. The supernatant solution was filtered througha 0.45 micron filter to remove any solids. A portion of the filtrate wasdiluted 100:1 with 50% aq. acetonitrile and analyzed by UPLC asdescribed above. A portion of the original API solution was filtered,diluted and analyzed by UPLC as a comparative standard.

Procedure for Determining the BAK Partition Coefficient

To a 20 ml scintillation vial was added 0.2 g of the OxPO being testedand 5.0 ml of a 1000 ppm BAK solution in normal PBS. The vial was cappedand swirled on a rotary shaker for 48 hrs. The supernatant solution wasfiltered through a 0.45 μm filter to remove any solids. A portion of thefiltrate was diluted 1:1 with acetonitrile and analyzed by UPLC asdescribed above. To calculate the ratio of the BAK adsorbed on the OxPOto the BAK remaining in the solution, the following formula was used(PC=partition coefficient):PC=[(initial BAK conc.−final BAK conc.)×wt. of solution]/wt. ofOxPO×final BAK conc.For example, if the initial BAK concentration was 1000 ppm, the finalBAK concentration was 14 ppm, using 5.0 g of solution and 0.20 g of OxPOpowder, the PC=1761. In this test PC values >50 are desired; values >100are preferred and values >1000 demonstrated nearly complete adsorptionof BAK.Summary of BAK Partition Coefficients for OxPOs

The partition coefficient test described above was used to determine thevalues for OxPOs that were classified to various particle sizes, washedwith neutral, acidic or basic solutions and dried.

Particle Acid size Wash BAK Part. Type of material source No. (μm)solution coefficient polymer A-C 395 Honeywell 40 125-250 unwashed 54OxHDPE A-C 395 Honeywell 40 125-250 neutral 1100 OxHDPE A-C 395Honeywell 40  63-125 0.1N 1813 OxHDPE AcOH A-C 395 Honeywell 40  63-1250.1N 113 OxHDPE NH₄OH A-C 330 Honeywell 30 mixture neutral 59 OxHDPE EO45K Deurex 25 125-500 neutral 71 OxHDPE EO 45K Deurex 25 125-500 0.1N 81OxHDPE AcOH TO 84 Deurex 30-40 125-250 unwashed 2,475 OxFTW TO 84 Deurex30-40 125-250 0.1N 11,880 OxFTW AcOH LDPE Alfa Aesar 0 500 unwashed 0LDPE #A10239 LDPE Alfa Aesar 0 500 0.1N 0.2 LDPE #A10239 AcOHPreparation of Combination Timolol Maleate and Dorzolamide HydrochlorideOphthalmic Solution

To 60.0 g of ultrapure water was added 0.090 g hydroxyethyl cellulose(Natrosol 250H) and the solution was stirred overnight to dissolve.Subsequently, 0.176 g sodium citrate dihydrate and 0.960 g mannitol wereadded and the mixture was stirred until completely dissolved. 1.37 gDorzolamide Hydrochloride, 0.420 g Timolol Maleate and 0.045 g of a 10%aqueous solution of BAK were added and incorporated. The pH was adjustedto 5.65 with 0.01N NaOH solution. The final nominal concentrations arereported below.

Component Conc. % (w/v) API conc. Timolol Maleate (0.5% free base) 0.6835.00 mg/ml Dorzolamide Hydrochloride (2.0% 2.26 20.0 mg/ml free base)BAK (70/30 C12/C14) 0.0075   75 μg/ml Sodium Citrate dihydrate 0.2941Mannitol 1.6Procedure for Packing Dropper Tips with OxPO

An empty dropper tip equipped with a 25 μm filter at the tip exit waspacked with approximately 0.40-0.45 mg of OxPO and the backing filterwas attached to retain the OxPO packing in place. The weight of the OxPOpacking was recorded. The packed tip was then inserted into the neck ofan 8 ml dropper bottle containing 5 ml of the API/BAK test solution.

30 Day Drop Test for Combination Timolol/Brimonidine/BAK Formulation

5 ml of the formulation described above containing nominally 5.0 mg/mlTimolol, 20.0 mg/ml Dorzolamide and 75 μg/ml BAK was loaded into sixeyedropper bottles packed with OxHDPE (A-C 395, 125-250 μm, acid washed)as described above. Drops were obtained from each bottle twice a day (AMand PM 8 hours apart) and analyzed by HPLC for API and BAK. The resultsare summarized in the table below. This experiment demonstrated theability of the OxPO to remove >95% of the BAK and retain >95% of the APIover the 30-day test period.

30-day Drop Test Summary Day BAK Timolol Dorzolamide Initial 75 (μg/ml)5.04 (mg/ml) 21.0 (mg/ml)  1A 0.088 4.93 20.0  1P ND 4.91 20.1  2A ND4.51 19.2  2P ND 4.64 19.4  3A ND 4.60 19.5  3P ND 4.65 19.6  4A ND 4.5919.3  4P ND 4.72 19.7  5A ND 4.68 19.7  5P ND 4.78 19.8  6A ND 4.76 19.8 6P ND 4.90 20.2  7A ND 4.86 20.3  7P ND 4.91 20.3  8A ND 4.85 20.1  8PND 4.89 20.2  9A ND 4.84 19.8  9P ND 4.87 19.5 10A ND 4.89 19.8 10P ND4.90 20.1 11A ND 4.89 19.9 11P ND 4.96 19.9 12A ND 4.86 19.8 12P ND 4.9519.9 13A ND 4.89 19.9 13P ND 4.93 19.9 14A ND 4.86 19.7 14P ND 4.97 20.015A ND 4.87 19.8 15P ND 4.93 19.9 16A ND 4.90 19.5 16P ND 5.01 19.8 17AND 4.90 19.4 17P ND 4.97 19.4 18A ND 4.98 19.7 18P ND 4.97 19.6 19A ND4.87 19.2 19P ND 4.98 19.5 20A ND 4.99 19.6 20P ND 5.02 19.7 21A ND 4.9219.6 21P ND 4.95 19.7 22A ND 4.98 20.0 22P ND 4.93 19.5 23A ND 4.96 19.823P ND 4.97 19.8 24A ND 4.94 19.8 24P ND 4.96 19.8 25A ND 4.90 19.6 25PND 4.93 19.7 26A ND 4.97 20.2 26P ND 4.96 20.1 27A ND 4.96 20.1 27P ND4.97 20.1 28A ND 4.93 20.1 28P ND 4.95 19.9 29A ND 4.90 19.6 29P ND 4.9319.6 30A ND 4.98 20.1 30P ND 4.97 20.1 A = 1st set of day P = 2nd set ofday ND = None DetectedIllustrative solutions, emulsions, or suspensions which can be used inaspects of the pharmaceutical formulation disclosed herein are shown inTables 1 to 4. Example solutions, emulsions, or suspensions in thetables above may be integrated into preservative removing devices andmethods of removing a preservative of the present disclosure. One ormore embodiments, variations, and examples of the preservative removingdevices, matrices, and methods described herein may be incorporated intoan eye drop dispensing system, which system may comprise a squeezablebottle. A squeezable bottle may comprise a reservoir in which a fluidmay be stored. A fluid stored in the reservoir may comprise anembodiment, variation, or example of solutions, emulsions, orsuspensions described herein, including those examples provided inTables 1 to 4.

All patents, patent applications, provisional applications, andpublications referred to or cited herein are incorporated by referencein their entirety, including all figures and tables, to the extent theyare not inconsistent with the explicit teachings of this specification.

It should be understood that the examples and embodiments describedherein are for illustrative purposes only and that various modificationsor changes in light thereof will be suggested to persons skilled in theart and are to be included within the spirit and purview of thisapplication.

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. It is not intendedthat the invention be limited by the specific examples provided withinthe specification. While the invention has been described with referenceto the aforementioned specification, the descriptions and illustrationsof the embodiments herein are not meant to be construed in a limitingsense. Numerous variations, changes, and substitutions will now occur tothose skilled in the art without departing from the invention.Furthermore, it shall be understood that all aspects of the inventionare not limited to the specific depictions, configurations or relativeproportions set forth herein which depend upon a variety of conditionsand variables. It should be understood that various alternatives to theembodiments of the disclosure described herein may be employed inpracticing the invention. It is therefore contemplated that theinvention shall also cover any such alternatives, modifications,variations or equivalents. It is intended that the following claimsdefine the scope of the invention and that methods and structures withinthe scope of these claims and their equivalents be covered thereby.

What is claimed is:
 1. A particulate plug for removing a preservativefrom a solution, suspension, or emulsion comprising a drug, theparticulate plug comprising microparticles of a polymer comprisingoxidized polyolefin (OxPO) wherein the microparticles form a particulateplug having a hydraulic permeability greater than 0.01 Da, wherein theparticulate plug formed from the microparticles of the polymercomprising the OxPO has a partition coefficient for the preservativethat is greater than a partition coefficient for the drug.
 2. Theparticulate plug of claim 1, wherein the oxidized polyolefin (OxPO) isselected from a homopolymer or copolymer of ethylene, propylene,1-butene, 4-methyl-1-pentene, 3-methyl-1-butene, 4,4-dimethyl-1-pentene,3-methyl-1-pentene, 4-methyl-1-hexene, 5-ethyl-1-hexene,6-methyl-1-heptene, 1-hexene, 1-heptene, 1-octene, 1-nonene, or1-decene.
 3. The particulate plug of claim 1, wherein the oxidizedpolyolefin (OxPO) is a homopolymer or a copolymer of oxidized highdensity polyethylene (OxHDPE).
 4. The particulate plug of claim 1,wherein the oxidized polyolefin (OxPO) is a polymer formed by theFischer-Tropsch process.
 5. The particulate plug of claim 1, wherein thedrug is selected from timolol maleate, levofloxacin, dorzolamide,brimonidine tartrate, or a combination thereof.
 6. The particulate plugof claim 1, wherein the preservative comprises: benzalkonium chloride(BAK); a quaternary ammonium compound; a solution of borate, sorbitol,propylene glycol, and zinc; or stabilized oxychloro complexes.
 7. Theparticulate plug of claim 1, wherein the particulate plug comprises apacked bed of particles.
 8. The particulate plug of claim 1, wherein theparticulate plug is sintered to fuse the particulate plug as a porousmonolith.
 9. The particulate plug of claim 1, wherein the particulateplug is pre-equilibrated with the solution, suspension, or emulsion. 10.The particulate plug of claim 1, wherein the OxPO comprises an acidvalue of about 41 mg KOH/g.
 11. The particulate plug of claim 1, whereinthe OxPO comprises a drop point between 125 and 135 Celsius.
 12. Theparticulate plug of claim 1, wherein the OxPO comprises a density ofabout 0.98 grams per cubic centimeter.
 13. The particulate plug of claim1, wherein the OxPO comprises a viscosity of 4.00 mPas at 190 Celsius.14. The particulate plug of claim 1, wherein the microparticles of thepolymer comprising OxPO are sized between 125 and 250 microns.
 15. Theparticulate plug of claim 1, wherein the drug comprises a hydrophilicdrug.
 16. The particulate plug of claim 1, wherein the OxPO comprises anacid value of at least 20 mg KOH/g.
 17. The particulate plug of claim16, wherein the OxPO comprises an acid value of at least 30 mg KOH/g.18. A method of removing a preservative from a drug solution,suspension, or emulsion, comprising: providing a container having anextended outlet and a chamber for holding the drug solution, suspension,or emulsion comprising at least one drug and a preservative, thecontainer comprising a particulate plug within the extended outlet,wherein the particulate plug comprises microparticles of a polymercomprising oxidized polyolefin (OxPO), and wherein the microparticlesform a particulate plug having a hydraulic permeability greater than0.01 Da; and forcing the drug solution, suspension, or emulsion throughthe particulate plug, wherein the particulate plug selectively removes apreservative from the solution, emulsion, or suspension.
 19. The methodof claim 18, wherein the particulate plug has a partition coefficientfor the preservative that is greater than a partition coefficient forthe at least one drug.
 20. The method of claim 18, wherein theparticulate plug has a partition coefficient for the preservative thatis at least 100 and a partition coefficient for the at least one drugthat is less than
 1. 21. The method of claim 18, wherein the containeris an eye drop bottle comprising a holder assembly configured to retainthe particulate plug.
 22. The method of claim 21, wherein the holderassembly comprises a formulation entry face and a formulation exit faceand wherein the formulation entry face and the formulation exit facecomprise filters.
 23. The method of claim 21, wherein the holderassembly comprises a solution, suspension, or emulsion permeable bagaround the particulate plug.